多药耐药基因单倍体对中国癫痫患者丙戊酸钠血药浓度的影响

Effects of the multidrug resistance 1 gene haplotype on resistance of valproic acid in Chinese Han Epilepsy patients

目的:探讨多药耐药基因(MDR1)C1236T、C3435T、G26677T/A 3个SNP位点单倍型对中国汉族癫痫患者丙戊酸钠血药浓度的影响。方法:实验选择单药服用丙戊酸钠的汉族癫痫患者143例,根据临床资料分为耐药组(n=68)和控制组(n=75),应用Pyrosequencing法测定MDR1基因C1236T、C3435T、G26677T/A多态性,同时应用荧光偏振免疫法(FPIA)测定耐药组和控制组患者丙戊酸钠的血药浓度。结果:耐药组C3435T位点CC型发生率(66.18%)高于控制组(26.03%)(P<0.01),而CT型发生率(19.12%)则低于控制组(60.27%)(P<0.05),耐药组C1236T CT型(23.53%)低于控制组(45.33%)(P<0.05);单倍体分析结果表明,丙戊酸钠耐药组单倍型CGC(18.38%)高于控制组(9.33%)(P<0.05);单倍型TTT(10.29%)低于控制组(17.33%)(P<0.05);血药浓度检测结果表明:CGC型的血药浓度高于控制组,两组资料间血药浓度均值的差别有统计学意义(P<0.05)。结论:MDR1基因CGC单倍型影响癫痫患者丙戊酸钠血药浓度,可能是引起丙戊酸钠耐药的影响因素。

AIM：To investigate the association between valproic acid（VAP） plasma concentration and the multidrug resistance 1（MDR1）gene linkage disequilibrium among C1236T-G2677T-C3435T in Chinese Epilepsy Patients. METHODS：The study consisted of 143 epileptic patients receiving sodium valproate.The patients were divided into two groups according to the date of clinic.One was drug fast group（n=68）and the other was control group（n=75）.The C1236T,C3435T and G2677T/A SNPs of MDR1 gene were determined by Pyrosequencing and sequencing analysis.Fluorescence polarization immunoassay（FPIA） was used to measure the serum concentration of sodium valproate.RESULTS：Incidence rate of CC for C3435T in drug fast group（66.18%）was higher than that in control group（26.03%）（P0.001）;Incidence rate of CT for C3435T in drug fast group（19.12%）was higher than that in control group（60.27%）（P0.05）;Incidence rate of CT for C1236T in drug fast group（23.53%）was lower than that in control group（45.33%）（P0.05）;Incidence rate of CGC in drug fast group（18.38%）was higher than that in control group（9.33%）（P0.05）;Haplotypes analysis demonstrated that the incidence rate of TTT in drug fast group（10.29%）was lower than that in control group（17.33%）（P0.05）;The mean value of the serum concentration of sodium valproate in CGC drug fast group was higher than that in CGC control group with a statistical significance（P0.05）.CONCLUSION：The haplotype of CGC of MDR1 affect the serum concentration of sodium valproate,it offers a potential mechanistic basis to explain intersubject difference in drug fast of sodium valproate.